The goal of this research is to achieve tumor specific delivery of radiosensitizing drugs by use of ligands that bind to radiation-inducible receptors within cancer. Synopsis. The tumor vascular endothelium responds to ionizing radiation in a similar manner in all tumor models. We, therefore, utilized phage displayed libraries to select peptide ligands that bind within the microvasculature of several classes of tumor models. We have screened 12 different peptide libraries that consist of varying lengths of both linear and cyclic peptides displayed upon phage. We have completed side-by-side comparisons of tumor-specific phage and found that the phage-displayed HGDPNHVGGSSV peptide ligand has sustained binding (9 days) within the tumor microvasculature following treatment with low dose irradiation. This peptide ligand clears from the circulation within 48 hours and binds specifically within tumors for nine days. Tumor sections show that the peptide binds to the tumor vascular endothelium. Our Preliminary Results show that biotinylated-HGDPNHVGGSSV precipitates an endothelial protein that will be identified in Aim 1. PHS 398 (Rev. 04/06) Principal Investigator: Hallahan, Dennis E. PROJECT NARRATIVE: In the proposed Aims, we will characterize the mechanism of HGDPNHVGGSSV binding within irradiated microvasculature. We will also study the effectiveness of this peptide at achieving tumor specific drug delivery within the microvasculature of irradiated tumors by means of a nanoparticulate delivery vehicle. Finally, we will deliver a gene expression system (radiosensitizing protein) to the endothelium site and study targeting and biological effects of the gene product. We envision that radiation sensitizing drugs can be targeted specifically to tumor micro-vasculature by use of peptide conjugated drug delivery systems during radiotherapy. The proposed Aims will test the hypothesis that HGDPNHVGGSSV peptide-conjugated nanoparticles provide tumor specific targeting of drug delivery to irradiated tumors. We will also test the hypothesis that the HGDPNHVGGSSV peptide binds to radiation-inducible proteins on the tumor microvascular endothelium.